Obesity is one of root causes of the onset of diabetes. A large number of obese individuals develop a peripheral resistance (insulin resistance) to the action of insulin before the onset of diabetes. It has been indicated that changes in the expression of various adipokines secreted from fat tissues is involved with the induction of insulin resistance. Enlargement of adipocytes is recognized in obese individuals and it has been known that enlarged adipocytes secrete a large amount of adipokines such as cytokines like TNF-α and resistin and free fatty acid and that the adipokines block the transduction of insulin signals in skeletal muscle and liver, inducing insulin resistance (Non-Patent Literatures 1 and 2).
From recent studies, it is believed that although inactive M2 macrophages produce IL-10, which is an anti-inflammatory cytokine, and arginase which suppresses NO biosynthesis to suppress inflammatory changes in non-obese visceral fat tissues, if active M1 macrophages increase due to obesity, inflammatory cytokines such as TNF-α and IL-6 are secreted, promoting inflammatory changes in fat tissues.
It is known that M1 macrophages are almost unrecognizable in non-obese visceral fat tissues while the number of infiltrating M1 macrophages increases due to obesity. M1 macrophages in fat tissues strongly express inflammatory cytokines such as TNF-α, IL-6, and MCP-1, and oxidative stress-related genes such as iNOS. Therefore, it is believed that M1 macrophages promote chronic inflammation and oxidative stress of visceral fat tissues and play an important role in the onset of insulin resistance due to obesity.
In non-obese fat tissues, M2 macrophages are diffusely present. The number of M2 macrophages does not increase due to obesity. Although few reports have been made on the effect of M2 macrophages on insulin sensitivity, it is inferred that M2 macrophages are involved with maintenance/improvement of insulin sensitivity. It has been reported that M2 macrophages strongly express genes different from M1 macrophages, such as IL-10, arginase-1, Mrc1, YM1, and CD209, and that one of anti-inflammatory cytokines, IL-10, enhances insulin signaling in cultured adipocytes (Non-Patent Literature 3). Arginase, which is strongly expressed in M2 macrophages, acts competitively to iNOS. Since the oxidative stress of obese fat tissues promotes insulin resistance, it is thought that M2 macrophages highly expressing arginase are likely to be involved with improvement of insulin resistance.
A molecular mechanism of insulin signal transduction is under extensive study. Pathways called as insulin signal transduction pathways are normally known as a signal transduction system (PI3K-Akt system) from binding of insulin to an insulin receptor causing autophosphorylation of the receptor and leading to IRS (insulin receptor substrate), PI3K (Phosphoinositide 3 kinase), and Aid, and a pathway (MAPK pathway) from binding of insulin to an insulin receptor causing autophosphorylation of the receptor and going through activation of MAPK (mitogen-activated protein kinase). The PI3K-Akt system is thought to be important for changes in glucose metabolism.
A biguanide agent, which mainly suppresses gluconeogenesis in liver, and a thiazolidine derivative, which improves insulin sensitivity in muscles and fat tissues, have been developed as pharmaceutical agents improving insulin resistance and already been approved and used as antidiabetic drugs. The thiazolidine derivatives represented by pioglitazone are believed to activate as a ligand a peroxisome proliferator-activated receptor (PPAR) that is a nuclear receptor transcription factor, induce small adipocytes with high insulin sensitivity from enlarged adipocytes, and promote differentiation of adipocytes, thereby improving the insulin resistance (Non-Patent Literatures 4 to 7). Reports have also been made that indicate a possibility of an antagonist of PPARγ to improve the insulin resistance (Non-Patent Literatures 8 to 10). In addition, the followings have been disclosed as insulin resistance improving agents: an agent for improving insulin resistance containing adiponectin or a gene thereof as an active ingredient (Patent Literature 1); a preventive and/or therapeutic agent for diseases caused by insulin resistance containing a substance having affinity to bombesin receptor subtype 3 (BRS-3) as an active ingredient (Patent Literature 2); a free fatty acid (FFA) reducing agent containing a pyrrole derivative as an active ingredient (Patent Literature 3), etc.
Although various insulin resistance improving drugs have been reported as described above, the causes of obesity and insulin resistance have not yet completely been clarified, and it is desired to clarify unknown pathways or mechanisms leading to obesity or insulin resistance and to develop new pharmaceutical drugs targeting such pathways or mechanisms.